The present invention relates to hydroxycarbonyl-halogenoalkyl derivatives designed to significantly increase oral activity of compounds having low activity following oral administration, compounds having anti-tumor activity, compounds having estrogenic activity or compounds having anti-estrogenic activity.
In treating diseases caused by abnormal tissue growth that is dependent upon a certain sexual steroidal hormone such as estrogen, it is highly important to significantly inhibit, more preferably completely eliminate, the effect induced by the hormone. For this purpose, it is desirable to reduce the level of hormone capable of acting on the steroidal hormone receptor site. For instance, anti-estrogenic agents are commonly administered for alternative or combination therapy to limit the production of estrogen to the amount less than required to activate the receptor site. However, such conventional technique for blocking estrogen production could not sufficiently inhibit the effect induced through the estrogen receptor. Practically, even when estrogen is completely absent, some of the receptors may be activated. It was therefore considered that estrogen antagonists could provide better therapeutic effect in comparison to the technique for blocking only the production of sexual steroidal hormone. Thus, numerous estrogen antagonists have been developed. For example, many patent publications including U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661, 5,395,842 and WO 96/22092 disclose various anti-estrogenic compounds. Sometimes, however, prior art antagonists may themselves act as agonists, and therefore activate rather than block the receptor. For example, Tamoxifen has been most widely used as an anti-estrogenic agent. However, this agent has a disadvantage that it exhibits estrogenic activity in some organs (see, M. Harper and A. Walpole, J. Reprod. Fertile., 1967, 13, 101).
As another non-steroidal anti-estrogenic compound, WO 93/10741 discloses a benzopyran derivative having an aminoethoxyphenyl substituent(s) (Endorecherche), the typical compound of which is EM-343 having the following structure: 
Said compound also has the agonistic effect. It is therefore required to develop an anti-estrogenic compound which is substantially or completely free of agonistic effect and which can effectively block the estrogen receptor.
In addition, it has been known that 7xcex1-substituted derivatives of estradiol, for example, 7xcex1-(CH2)10CONMeBu derivatives, are steroidal anti-estrogenic agents without agonistic effect (see, EP-A 0138504, U.S. Pat. No. 4,659,516). Further, an estradiol derivative having a 7xcex1-(CH2)9SOC5H6F5 substituent has also been disclosed as a 7xcex1-substituted derivative of estradiol (see, Wakeling et al., Cancer Res., 1991, 51, 3867).
Non-steroidal anti-estrogenic agents without agonistic effect have been first reported by Wakeling et al. in 1987 (see, A. Wakeling and Bowler, J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661 discloses phenol derivatives having anti-estrogenic activity. These phenol derivatives generally have a naphthalene scaffold and include, typically, the following compounds: 
Some chroman and thiochroman derivatives have been reported as anti-estrogenic compounds having no agonistic effect (WO 98/25916). Although the existing anti-estrogenic compounds having no agonistic effect show a substantial therapeutic effect when administered via intravenous or subcutaneous injection, they show a highly reduced therapeutic effect when administered orally, due to their low bioavailability by oral route. Therefore, for convenience""s sake in the case of administration, it is desired to develop anti-estrogenic compounds which show a sufficient effect when administered orally and at the same time have no agonistic effect. Also, it is generally desired to develop agents which show a sufficient effect when administered orally.
The object of the present invention is to provide hydroxycarbonyl-halogenoalkyl derivatives designed to significantly increase oral activity of compounds having low activity following oral administration, compounds having anti-tumor activity, compounds having estrogenic activity or compounds having anti-estrogenic activity by enhancing their absorption from the intestinal tract and/or improving their stability against metabolism.
Our research efforts were directed to achieving the above object, and we have found that a side chain of general formula (1) allowed estrogenic compounds to show a significantly increased activity by oral route when attached to the parent scaffolds of the compounds. The present invention has been accomplished on the basis of this finding.
Namely, the present invention provides a compound consisting-of a moiety and a group chemically bonded to said moiety, wherein said moiety contains a compound having low activity following oral administration or its parent scaffold and said group has the following general formula (1): 
in which
R1 represents a hydrogen atom or a salt-forming metal,
R2 represents a linear or branched C1-C7 halogenoalkyl group,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or enantiomers of the first-mentioned compound, or hydrates or pharmaceutically acceptable salts of the compound or enantiomers thereof.
The present invention also provides a compound consisting of a moiety and a group chemically bonded to said moiety, wherein said moiety contains a compound having anti-tumor activity or its parent scaffold and said group has the following general formula (1): 
in which
R1 represents a hydrogen atom or a salt-forming metal,
R2 represents a linear or branched C1-C7 halogenoalkyl group,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or enantiomers of the first-mentioned compound, or hydrates or pharmaceutically acceptable salts of the first-mentioned compound or enantiomers thereof.
The present invention further provides a compound consisting of a moiety and a group chemically bonded to a moiety, wherein said moiety contains a compound having estrogenic activity or its parent scaffold or a compound having anti-estrogenic activity or its parent scaffold and said group has the following general formula (1): 
in which
R1 represents a hydrogen atom or a salt-forming metal,
R2 represents a linear or branched C1-C7 halogenoalkyl group,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or enantiomers of the first-mentioned compound, or hydrates or pharmaceutically acceptable salts of the first-mentioned compound or enantiomers.
The present invention even further provides a compound having the following general formula (2): 
in which
R1 represents a hydrogen atom or a salt-forming metal,
R2 represents a linear or branched C1-C7 halogenoalkyl group,
m represents an integer of 2 to 14,
n represents an integer of 2 to 7, and
A represents a group selected from the following formulae (3) to (8) and (10) to (26): 
in which
in formulae (6), (7), (14) and (24), each of R3 and R6 represents a linear or branched C1-C5 alkyl group,
in formulae (10), (11) and (12), Z10 represents a hydrogen atom or an acyl group,
in formulae (13), (21) and (22), each of Z1, Z2, Z3, Z4, Z5 and Z6 independently represents a hydrogen atom, a hydroxyl group or a linear or branched C1-C5 alkyl group,
in formula (15), R7 represents a hydrogen atom or a linear or branched C1-C5 alkyl group,
in formula (16), each of Z7, Z8, and Z9 independently represents a hydrogen atom or a hydroxyl group,
in formulae (18) and (20), R8 represents a linear or branched C1-C5 alkyl group, a linear or branched C2-C5 alkenyl group or a linear or branched C2-C5 alkynyl group,
in formula (23), each of R21, R22, R23 and R24 independently represents a hydrogen atom, a linear or branched C1-C5 alkyl group, a linear or branched C1-C7 halogenoalkyl group, a halogen atom or an acyl group, and
in formulae (25) and (26), X represents a halogen atom,
or enantiomers of the compound, or hydrates or pharmaceutically acceptable salts of the compound or enantiomers thereof.
Furthermore, the present invention provides a pharmaceutical composition comprising a compound of general formula (2) as an active ingredient. The present invention also provides an anti-estrogenic pharmaceutical composition comprising the above compound as an active ingredient. The present invention further provides a therapeutic agent for breast cancer comprising a compound of general formula (2) as an active ingredient.
As used herein, the term xe2x80x9cparent scaffold(s)xe2x80x9d refers to a partial structure shared by a class of compounds having the same or similar pharmacological effects or physicochemical properties. The parent scaffolds include, but are not limited to, the following structures: steroid, indole, naphthalene, benzofuran, benzothiophene, benzopyran, benzoxazine, 3,4-diphenyl-[4.3.0]-nonane, 4-(1,2-diphenyl-1-butenyl)phenol, flavone, erythromycin, alkaloid, cephalosporin, xcex2-lactam, and derivatives thereof.
Compounds having low activity following oral administration refer to those compound which are incapable of showing adequate activity for a desired pharmacological effect when administered orally because they are poorly absorbed from the intestinal tract or rapidly metabolized in the body. Examples include certain types of anti-tumor compounds, certain types of estrogenic compounds (e.g., estradiol) and anti-estrogenic compounds.
Compounds having anti-tumor activity include all types of compounds capable of inhibiting tumor growth. The present invention is particularly advantageous to those compounds showing low activity by oral route.
Compounds having estrogenic activity refer to those compounds which have affinity for the estrogen receptor and enhance the signaling mediated by the estrogen receptor. Examples include estradiol.
Compounds having anti-estrogenic activity refer to those compounds which have an antagonistic activity against estrogen""s pharmacological effects. Examples include the compounds described in the prior art reports mentioned above.
The present invention provides compounds wherein a moiety is chemically bonded to a group, wherein said moiety containing a compound having low activity following oral administration, a compound having anti-tumor activity, a compound having estrogenic activity or a compound having anti-estrogenic activity or the parent scaffolds of these compounds and said group having the general formula (1). As used herein, the term xe2x80x9cchemically bondedxe2x80x9d means that the group is bonded through a covalent bond and the like, including a Cxe2x80x94C bond, a Cxe2x80x94O bond, a Cxe2x80x94N bond, etc. The moiety containing the above-mentioned compounds or their parent scaffolds may take any structure as long as these bonds are possible. A Cxe2x80x94C bond is preferably used to improve stability against metabolism and hence activity by oral route.
Salt-forming metals as R1 include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, rare earth metals such as cerium and samarium, as well as zinc and tin. Among these, alkali metals and alkaline earth metals are preferred.
R1 may preferably be a hydrogen atom, an alkali metal and an alkaline earth metal.
Halogens in the linear or branched C1-C7 halogenoalkyl groups as R2 include fluorine, chlorine, bromine and iodine, with fluorine being preferred. R2 may contain one or more halogen atoms. When R2 contains two or more halogen atoms, they may be the same or different, preferably the same halogen atoms. In particular, R2 is preferably a perhalogenoalkyl group. Alkyls in the linear or branched C1-C7 halogenoalkyl groups under consideration include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl and n-heptyl. Preferred are linear or branched C1-C4 alkyls, i.e., methyl, ethyl, n-propyl, i-propyl and n-butyl.
Examples of the linear or branched C1-C7 perhalogenoalkyl group as R2 include the above-listed linear or branched C1-C7 alkyl groups, provided that they are perhalogenated, preferably perfluorinated. Also preferred are perhalogenated linear or branched C1-C5 alkyl groups and a group of the following general formula (9): 
in which each of R4 and R5 which may be the same or different represents a linear or branched C1-C3 perhalogenoalkyl group. Among them, perfluorinated groups are preferred. More specifically, a perfluoromethyl group, a perfluoroethyl group, a perfluoro-n-propyl group and a perfluoro-n-butyl group are particularly preferred.
In the case where R2 in general formula (2) is a group of general formula (9), examples of the linear or branched C1-C3 perhalogenoalkyl group as R4 and R5 include the above-listed linear or branched C1-C3 alkyl groups, provided that they are perhalogenated, preferably perfluorinated. Further, perhalogenated C1 alkyl groups are preferred and a perfluorinated group is particularly preferred. More specifically, a perfluoromethyl group is preferred.
In the case where R2 in general formula (2) is a group of general formula (9), R2 is preferably a 1,1,1,3,3,3-hexafluoroisopropyl group.
Having the definition given above, R2 is preferably a perfluoroethyl group, a perfluoro-n-propyl group, a perfluoro-n-butyl group, and a 1,1,1,3,3,3-hexafluoro-isopropyl group.
Examples of the linear or branched C1-C5 alkyl group as used herein include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1-ethylpropyl.
Examples of the linear or branched C2-C5 alkenyl group as used herein include, but are not limited to, vinyl, allyl, 1-butenyl, 2-butenyl and 3-butenyl.
Examples of the linear or branched C2-C5 alkynyl group as used herein include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl and 3-butynyl.
Examples of the acyl group as used herein include, but are not limited to, alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, caproyl and phenylacetyl; alkenylcarbonyl groups such as acryloyl, propyoloyl, methacryloyl, crotonoyl and isocrotonoyl; and arylcarbonyl groups such as benzoyl.
Examples of the linear or branched C1-C7 halogenoalkyl group as R21, R22, R23 and R24 may be the same groups as previously listed for R2.
Group A may preferably be any one of the groups having formulae (3) to (8) and (10) to (23), particularly groups having formulae (3) to (6), (17) to (20) and (23), and more particularly groups having formulae (3), (4) and (17) to (20).
m may preferably be an integer of 4 to 10.
n may preferably be an integer of 2 to 7.
The group of general formula (1), which is one component of the compound according to the present invention, has an asymmetric center, while the other component may have an asymmetric center. Further, the compound of general formula (2) according to the present invention may have an asymmetric center in group A in addition to the asymmetric center in the group of general formula (1). For this reason, the compounds of the present invention have enantiomers. All individual enantiomers and mixtures thereof are intended to be within the scope of the present invention. When group A having an asymmetric center is a steroid scaffold represented by any one of formulae (3), (4) and (17) to (20), the group of general formula (1) is preferably attached to the steroid parent scaffold at 7xcex1- or 11xcex2-position.
Also, in the general formulae(1) and (2), both compounds with R- and S-configulation of the asymmetric carbon to which carboxylic acid or its metal salt is attached are preferable.
Among compounds of general formula (2), preferred are those compounds in which R1 is a hydrogen atom, an alkali metal or an alkaline earth metal; R2 is a perfluoroethyl group, a perfluoro-n-propyl group, a perfluoro-n-butyl group or a 1,1,1,3,3,3-hexafluoroisopropyl group; m is an integer of 4 to 10; and n is an integer of 2 to 6.
The compounds of the present invention may be obtained as hydrates.
Pharmaceutically acceptable salts include, but are not limited to, the above-mentioned metal salts, for example, sodium, potassium and calcium salts.
The compound according to the present invention may be administered as a pharmaceutical composition in any dosage form suitable for the intended route of administration, in combination with one or more pharmaceutically acceptable diluents, wetting agents, emulsifiers, dispersants, auxiliary agents, preservatives, buffers, binders, stabilizers and the like. The compound and composition may be administered parenterally or orally.
The dose of the compound can be suitably determined according to the physique, age and physical condition of a patient, severity of the disease to be treated, elapsed time after onset of the disease, etc. Because the compound of the present invention is expected to show a significantly high activity by oral route, it is generally used in an amount of 0.1 to 500 mg/day when orally administered and in an amount of 0.1-1000 mg/day to 0.1-1000 mg/month when parenterally administered (by intravenous, intramuscular, or subcutaneous route) for adult patient.
The compound of general formula (1), particularly the compound of general formula (2), can be prepared according to any one of the following Reaction Schemes A to K and 1 to 19. In these Reaction Schemes A to K and 1 to 19 (i.e., Processes A to K and 1 to 19), R2, R3, R6, R7, Z1, Z2, Z3, Z4, Z5. Z6, Z7, Z8, Z9, Z10, m and n are as defined above in general formulae (1) and (2); each of R11, R12, R13 and R16 represents a protecting group; R33 represents a linear or branched alkyl group; each of Y1, Y2, Y3, Y4, Y5 and Y6 independently represents a hydrogen atom, an alkyl group (e.g., a linear or branched C1-C5 alkyl group) or OR11; each of L1 and L2 represents a leaving group; X represents a halogen atom; m1 is mxe2x88x922; R8 represents a linear or branched C1-C5 alkyl group, a linear or branched C2-C5 alkenyl group or a linear or branched C2-C5 alkynyl group.
The compound of the present invention may include various stereoisomers because it contains one or more asymmetric carbon atoms. To obtain a single stereoisomer, there are two techniques, one of which uses a chiral column to resolve a mixture of stereoisomers and the other involves asymmetric synthesis. The chiral column technique may be carried out using a column commercially available from DAICEL under the trade name of CHIRALPAK-OT(+), OP(+) or AD, or CHIRALCEL-OA, OB, OJ, OK, OC, OD, OF or OG, for example. Regarding asymmetric synthesis, Processes 14 to 16 illustrate the asymmetric synthesis of the inventive compound with respect to an asymmetric carbon atom, to which a side chain carboxyl group is attached. 
Note: Compound (I) can be synthesized by the method described in J. Org. Chem., 60(1995) 5316-5318. 
Note: Compound (XXI) can be synthesized by the method described in DE4218743A1. 
in which
R8 represents a linear or branched C1-C5 alkyl group, a linear or branched C2-C5 alkenyl group or a linear or branched C2-C5 alkynyl group, and
M represents a metal. 
in which
R8 represents a linear or branched C1-C5 alkyl group, a linear or branched C2-C5 alkenyl group or a linear or branched C2-C5 alkynyl group, and
M represents a metal. 
in which
each of Y1, Y2 and Y3 independently represents a hydrogen atom, an alkyl group (e.g., a linear or branched C1-C5 alkyl group) or OR11, and
each of Z1, Z2 and Z3 independently represents a hydrogen atom, a hydroxyl group or a linear or branched C1-C5 alkyl group. 
in which
each of Y1, Y2, Y3, Y4, Y5 and Y6 independently represents a hydrogen atom, an alkyl group (e.g., a linear or branched C1-C5 alkyl group) or OR11, and
each of Z1, Z2, Z3, Z4, Z5 and Z6 independently represents a hydrogen atom, a hydroxyl group or a linear or branched C1-C5 alkyl group. 
In the above Reaction Schemes 14 and 15 (Processes 14 and 15), R2, R11, R12, X, m, n, X, L1 and L2 are as defined above, R* represents a chiral auxiliary, and m and M3 are integers that satisfy the relation m=m3+3. 
[Process A]
Process A illustrates the synthesis of compound (VI) starting with compound (I). Compound (I) can be synthesized by the method described in J. Org. Chem., 60(1995) 5316-5318.
Step 1: Preparation of Compound (III)
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (I) is reacted with compound (II) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (III).
Step 2: Preparation of Compound (IV)
Using a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound (III) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform or benzene) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (IV).
Step 3: Preparation of Compound (V)
When R11 is, for example, a methyl group, compound (IV) is treated with an acid (e.g., hydrogen chloride, sulfuric acid, hydrogen bromide, pyridine hydrochloride or boron tribromide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (V).
Step 4: Preparation of Compound (VI)
Compound (V) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or a water/methanol mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (VI).
[Process B]
As shown below, compound (VI) given by Process A can also be prepared starting with compound (I) in the following manner.
Step 1: Preparation of Compound (VIII)
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (I) is reacted with compound (VII) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (VIII).
Step 2: Preparation of Compound (IX)
Using a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound (VIII) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform or benzene) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (IX).
Step 3: Preparation of Compound (X)
Compound (IX) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or a water/methanol mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (X).
Step 4: Preparation of Compound (XI)
In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in the presence of an acid (e.g., hydrogen chloride, sulfuric acid or p-toluenesulfonic acid), compound (X) is heated to a temperature ranging from 50xc2x0 C. to the boiling point of the reaction mixture to give compound (XI).
Step 5: Preparation of Compound (VI)
When R11 is, for example, a methyl group, compound (XI) is treated with an acid (e.g., hydrogen chloride, sulfuric acid, hydrogen bromide, pyridine hydrochloride or boron tribromide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (VI).
[Process C]
As shown below, compound (VI) given by Processes A and B can also be prepared starting with compound (XII) in the following manner.
Step 1: Preparation of Compound (XIV)
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XII) is reacted with compound (XIII) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XIV).
Step 2: Preparation of Compound (IV)
Compound (XIV) is dehydrated using an acid (e.g., hydrochloric acid, hydrobromic acid, hydrobromic acid/acetic acid) in an inert solvent (e.g., methanol, ethanol) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at 50xc2x0 C., and further processed by hydrogenation analogous to Process A to give compound (IV).
Step 3: Preparation of Compound (VI)
Compound (IV) is subjected to hydrolysis and deprotection analogous to Process A or B to give compound (VI).
[Process D]
As shown below, compound (VI) given by Processes A, B and C can also be prepared starting with compound (XII) in the following manner.
Step 1: Preparation of Compound (XVI)
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XII) is reacted with compound (XV) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XVI).
Step 2: Preparation of Compound (XVII)
Compound (XVI) is dehydrated using an acid (e.g., hydrochloric acid, hydrobromic acid, hydrobromic acid/acetic acid) in an inert solvent (e.g., methanol, ethanol) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at 50xc2x0 C., and further processed by hydrogenation analogous to Process A to give compound (XVII).
Step 3: Preparation of Compound (VI)
Compound (XVII) is subjected to hydrolysis, decarboxylation and deprotection by a procedure analogous to Process A or B to give compound (VI).
Compound (XII) used as a starting material in Processes C and D can be prepared according to the method described in Tetrahedron., 30(1977) pp. 609-616.
[Process E]
Process E illustrates the synthesis of compound (XXIX) starting with compound (XXI).
Step 1: Preparation of Compound (XXII)
In the presence of an organic base (e.g., triethylamine or pyridine), compound (XXI) is treated with an acid chloride (e.g., methanesulfonyl chloride or p-toluenesulfonyl chloride) in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably dichloromethane) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to convert (CH2)mOH in compound (XXI) into (CH2)m-L1, in which L1 is xe2x80x94Oxe2x80x94SO2CH3 or xe2x80x94Oxe2x80x94SO2xe2x80x94C6H4-p-CH3, for example. The compound thus obtained is then treated with a metal halide (e.g., sodium iodide or potassium iodide) in an inert solvent (e.g., acetone, tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably acetone) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XXII).
Step 2: Preparation of Compound (XXIV)
In the presence of a base (e.g., sodium hydride, sodium hydroxide or potassium t-butoxide), compound (XXII) is reacted with a malonic ester (XXIII) (e.g., diethyl malonate or dimethyl malonate) in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature ranging from room temperature to the boiling point of the reaction mixture to give compound (XXIV).
Step 3: Preparation of Compound (XXVI)
In the presence of a base (e.g., sodium hydride, sodium hydroxide or potassium t-butoxide), compound (XXIV) is reacted with an alkyl halide (XXV), in which L2 represents a halogen atom, in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature ranging from room temperature to the boiling point of the reaction mixture to give compound (XXVI).
Step 4: Preparation of Compound (XXVII)
Compound (XXVI) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or a water/methanol mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XXVII).
Step 5: Preparation of Compound (XXVIII)
In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in the presence of an acid (e.g., hydrogen chloride, sulfuric acid or p-toluenesulfonic acid), compound (XXVII) is heated to a temperature ranging from 50xc2x0 C. to the boiling point of the reaction mixture to give compound (XXVIII).
Step 6: Preparation of Compound (XXIX)
When R11 is, for example, a methyl group, compound (XXVIII) is treated with an acid (e.g., hydrogen chloride, sulfuric acid, hydrogen bromide, pyridine hydrochloride or boron tribromide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (XXIX).
Compound (XXI) used as a starting material in Process E can be prepared according to the method described in DE4218743A1.
[Process F]
Compound (XXIX) given by Process E can also be prepared starting with compound (XXII) according to the following steps.
Step 1: Preparation of Compound (XXXI)
In the presence of a base (e.g., sodium hydride, sodium hydroxide or potassium t-butoxide), compound (XXII) is reacted with compound (XXX) in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (XXXI).
Step 2: Preparation of Compound (XXIX)
Compound (XXXI) is converted into compound (XXIX) by a procedure analogous to Process E.
[Process G]
Process G illustrates the synthesis of compound (ILVIII) starting with compound (ILI).
Step 1: Preparation of Compound (ILIII)
In the presence of a base (e.g., sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium hydride, preferably potassium carbonate), compound (ILI) is reacted with compound (ILII) in an inert solvent (e.g., acetone, methyl ethyl ketone, tetrahydrofuran, preferably acetone) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give compound (ILIII).
Step 2: Preparation of Compound (ILIV) via Claisen Rearrangement
Compound (ILIII) is dissolved in an inert solvent (e.g., N,N-dimethyl aniline, N,N-diethyl aniline, nitrobenzene, dichlorobenzene, dibromobenzene, preferably N,N-dimethyl aniline) and then heated to a temperature ranging from 180xc2x0 C. to the boiling point of the reaction mixture, preferably from 180xc2x0 C. to 200xc2x0 C., to give compound (ILIV).
Step 3: Preparation of Compound (ILV)
In the presence of a base (e.g., triethylamine, diethylisopropylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, preferably pyridine), compound (ILIV) is reacted with Tf2O (trifluoromethanesulfonic anhydride) in an inert solvent (e.g., dichloromethane, chloroform, benzene, toluene, preferably dichloromethane) at a temperature ranging from 0xc2x0 C. to room temperature to give compound (ILV).
Step 4: Preparation of Compound (ILVII)
In the presence of a palladium or nickel catalyst, compound (ILV) is reacted with compound (ILVI) in an inert solvent (e.g., ether, tetrahydrofuran, dioxane, dimethyl-formamide, water, preferably dioxane) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (ILVII).
Step 5: Preparation of Compound (ILVIII)
Compound (ILVII) is converted into compound (ILVIII) by a procedure analogous to Process A, B, C or D.
[Process H]
Process H illustrates the synthesis of compound (LIV) starting with compound (LI) synthesized by the method described in U.S. Pat. No. 4,904,661.
Step 1: Preparation of Compound (LII)
Compound (LI) is reacted with a reducing agent (e.g., lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride) in an inert solvent (e.g., tetrahydrofuran, dioxane, diethyl ether) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LII).
Step 2: Preparation of Compound (LIII)
In the presence of a suitable acid (e.g., zinc iodide, boron trifluoride), compound (LII) is reacted with allyl-trimethylsilane in an inert solvent (e.g., dichloroethane, dichloromethane, chloroform) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LIII).
Step 3: Preparation of Compound (LIV)
Compound (LIII) is subjected to analogous procedure to Process A, B, C or D, that is, metathesis, reduction, hydrolysis, decarboxylation, deprotection, etc. to give compound (LIV).
[Process I]
Compound (LIV) can also be synthesized starting with compound (LI) in the following manner.
Step 1: Preparation of Compound (LVI)
In the presence of a base (e.g., sodium hydride, n-butyllithium, t-butyllithium, lithium diisopropylamide, potassium tert-butoxide), compound (LI) is reacted with compound (LV) in an inert solvent (e.g., tetrahydrofuran, dioxane, diethyl ether) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C., to give compound (LVI).
Step 2: Preparation of Compound (LVII)
In the presence of a suitable acid (e.g., zinc iodide, boron trifluoride), compound (LVI) is reacted with sodium cyanoborohydride in an inert solvent (e.g., dichloroethane, dichloromethane, chloroform) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LVII).
Step 3: Preparation of Compound (LVIII)
In the presence of a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide), compound (LVII) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give compound (LVIII). Compound (LVIII) can be directly prepared form compound (LVI) through hydrogenation using a catalyst (e.g., palladium on activated carbon, palladium hydroxide or platinum oxide) in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature.
Step 4: Preparation of Compound (LIV)
Compound (LVIII) is reacted by a procedure analogous to Process E or F to give compound (LIV).
[Process J]
Process J illustrates the synthesis of compound (LXII) starting with compound (LIX).
Step 1: Preparation of Compound (LXI)
In the presence of a base (e.g., sodium hydride, n-butyllithium, potassium tert-butoxide), compound (LIX) is reacted with compound (LX) in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LXI).
Step 2: Preparation of Compound (LXII)
Compound (LXI) is subjected to metathesis, reduction, hydrolysis and deprotection by a procedure analogous to Process A, B, C or D to give compound (LXII).
[Process K]
Compound (LXII) can also be synthesized starting with compound (LIX) in the following manner.
Step 1: Preparation of Compound (LXIV)
In the presence of a base (e.g., sodium hydride, n-butyllithium, potassium tert-butoxide), compound (LIX) is reacted with compound (LXIII) in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LXIV).
Step 2: Preparation of Compound (LXII)
Compound (LXIV) is reacted by a procedure analogous to Process E or F to give compound (LXII).
Compounds of general formula (2) in which group A is represented by formula (8) can be prepared, for example, as shown in Examples 6 to 10 by the same or equivalent procedure.
[Process 1]
Compound 2 is prepared starting with compound 1 by a procedure analogous to Process E. Compound 1 used as a starting material can be prepared according to the method described in WO99/64393.
[Process 2]
Compound 4 is prepared starting with compound 3 by a procedure analogous to Process E. Compound 5 can be obtained by oxidizing compound 4 according to the method described in WO99/64393. Compound 3 used as a starting material can be prepared according to the method described in WO99/64393.
[Process 3]
Process 3 illustrates the synthesis of compound 9 starting with compound 6. Compound 6 used as a starting material can be synthesized by, for example, the methods described in J. Org. Chem., 50(1985) 2121-2123 and J. Org. Chem., 61(1996) 3890-3893.
Step 1: Preparation of Compound 8
In the presence of a base (e.g., sodium hydride, n-butyllithium, potassium tert-butoxide), compound 6 is reacted with compound 7 in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound 8.
Step 2: Preparation of Compound 9
Compound 8 is reacted by a procedure analogous to Process E to give compound 9.
[Process 4]
Process 4 illustrates the synthesis of compound 20 starting with compound 10.
Step 1: Preparation of Compound 11
In the presence of an acid catalyst such as sulfuric acid, compound 10 is heated in an alcohol (e.g., methanol, ethanol) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound 11.
Step 2: Preparation of Compound 12
Amino and hydroxyl groups of compound 11 prepared in Step 1 are protected to give compound 12.
Step 3: Preparation of Compound 13
Compound 12 is treated with a reducing agent (e.g., lithium borohydride, etc.) in a solvent (e.g., methanol, ethanol or ethanol/tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give compound 13.
Step 4: Preparation of Compound 15
Compound 13 is subjected to Mitsunobu reaction with compound 14 to give compound 15.
Step S: Preparation of Compound 16
Compound 15 is subjected to deprotection of the amino group to give compound 16.
Step 6: Preparation of Compound 17
In the presence of a base (e.g., potassium carbonate, potassium t-butoxide, sodium t-butoxide), compound 16 is reacted by addition of a metal catalyst such as palladium along with a ligand such as diphenylphosphino ferrocene or 2,2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, preferably by addition of a tris(dibenzylideneacetone)dipalladium catalyst along with 2,2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, in an inert solvent (e.g., benzene, toluene, xylene, dioxane or tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at 100xc2x0 C., to give compound 17.
Step 7: Preparation of Compound 19
In the presence of a base (e.g., sodium hydride, n-butyllithium, potassium tert-butoxide, potassium carbonate) and, if necessary, by addition of a reagent such as sodium iodide, compound 17 is reacted with compound 18 in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide, acetone) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound 19.
Step 8: Preparation of Compound 20
Compound 19 is reacted by a procedure analogous to Process A or B to give compound 20.
[Process 5]
Process 5 illustrates the synthesis of compound 27 starting with compound 21.
Step 1: Preparation of Compound 23
Compound 21 is subjected to protection with TBS, then reacted with aldehyde 22, and then protected at its amino group, to give compound 23.
Step 2: Preparation of Compound 25
Compound 23 prepared in Step 1 is alkylated with compound 24 to give compound 25.
Step 3: Preparation of Compound 26
Compound 25 is subjected to deprotection of the amino group and then treated with a reducing agent (e.g., lithium aluminum hydride, etc.) in a solvent (e.g., tetrahydrofuran, ether) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give compound 26.
Step 4: Preparation of Compound 27
Compound 26 is reacted by a procedure analogous to Process 4 to give compound 27.
[Process 6]
Process 6 illustrates the synthesis of compound 35 starting with compound 28.
Compound 35 can be synthesized starting with compound 28 in the following manner.
Step 1: Preparation of Compound 29
Compound 29 is prepared from compound 28 by the method described in Synthesis, 12(1995) 1493-1495 or by an equivalent method.
Step 2: Preparation of Compound 32
In the presence of a base (e.g., lithium hexamethyl-disilazide, sodium hexamethyl-disilazide, potassium hexamethyl-disilazide, sodium hydride, n-butyllithium, t-butyllithium, lithium diisopropylamide, potassium tert-butoxide, aqueous potassium hydroxide, aqueous sodium hydroxide), compound 29 is reacted with compound 30 or 31 in an inert solvent (e.g., 1,2-dimethoxyethane, tetrahydrofuran, dioxane, t-butyl methyl ether, diethyl ether, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, toluene) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C., to give compound 32.
Step 3: Preparation of Compound 33
Compound 32 is isomerized under a basic condition (e.g., tetrabutylammonium fluoride/tetrahydrofuran, sodium methoxide/methanol, sodium ethoxide/ethanol, potassium methoxide/methanol, sodium methoxide/propanol, aqueous potassium hydroxide, aqueous sodium hydroxide), followed by deprotection of R12 and purification via recrystallization, to give a single isomer of formula 33. In the case where R12 is a t-butyldimethylsilyl group, compound 32 is isomerized simultaneously with the removal of TBS by treatment with tetrabutylammonium fluoride and further purified via recrystallization to give the single isomer of formula 33.
Step 4: Preparation of Compound 34
In the presence of a suitable acid (e.g., trifluoroacetic acid, boron trifluoride etherate, titanium tetrachloride, aluminum chloride, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid), compound 33 is reacted with triethylsilane in an inert solvent (e.g., dichloroethane, dichloromethane, chloroform, t-butyl methyl ether, toluene) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound 34.
Step 5: Preparation of Compound 35
Compound 34 is reacted by a procedure analogous to Process A or B to give compound 35.
[Process 7]
Process 7 illustrates the synthesis of compound 38 starting with compound 36.
Compound 38 can be synthesized starting with compound 37 by a procedure analogous to Process 3. Compounds 36 and 37 used as starting materials can be synthesized by the methods described in J. Med. Chem., 40(1997) 2117-2122 and J. Med. Chem., 33(1990) 3222-3229 or by equivalent methods.
[Process 8]
Process 8 illustrates the synthesis of compound 40 starting with compound 39.
Compound 40 can be synthesized starting with compound 39 by a procedure analogous to Process 3. Compound 39 used as a starting material can be synthesized by, for example, the methods described in EP0826670A1 and J. Org. Chem., 60(1995) 739-741.
[Process 9]
Compound 42 or 43 can be synthesized in the following manner. Compound 42 can be synthesized from compound 41 by Jones oxidation, PCC oxidation, Swern oxidation, or ruthenium oxidation (e.g., TPAP) of the 17-hydroxyl group. Compound 42 is further reacted with R8-M, in which R8 represents a lower alkyl group or a lower alkenyl group or a lower alkynyl group and M represents a metal such as lithium, sodium, potassium, magnesium, calcium or aluminum, in an inert solvent (e.g., dimethyl sulfoxide, tetrahydrofuran, ether, dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound 43.
Compound 41 used as a starting material can be synthesized by Process E, F or 6.
[Process 10]
Compound 45 or 46 can be synthesized in the following manner. Compound 45 can be synthesized from compound 44 by Jones oxidation, PCC oxidation, Swern oxidation, or ruthenium oxidation (e.g., TPAP) of the 17-hydroxyl group. Compound 45 is further reacted with R8-M, in which R8 represents a lower alkyl group or a lower alkenyl group or a lower alkynyl group and M represents a metal such as lithium, sodium, potassium, magnesium, calcium or aluminum, in an inert solvent (e.g., dimethyl sulfoxide, tetrahydrofuran, ether, dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound 46.
Compound 44 used as a starting material can be synthesized by Process A, B, C or D.
[Process 11]
Compound 53 can be synthesized in the following manner.
Compound 47 is subjected to protection of its hydroxyl groups, and then oxidized between 9- and 11-position using DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) and the like to give compound 48.
Compound 48 is converted into compound 49 by the method described in J. Org. Chem., 1995, 60, 5316-5318.
Compound 49 is subjected to Swern oxidation, Jones oxidation, PCC oxidation, or ruthenium oxidation (e.g., TPAP) to give compound 50.
Compound 50 is reacted with an organometallic reagent (e.g., allylmagnesium halide) in an inert solvent (e.g., tetrahydrofuran, ether) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9248xc2x0 C. to room temperature, to give compound 51.
Compound 51 is dehydrated to remove its hydroxyl group using thionyl chloride/pyridine and the like to give compound 52.
Compound 52 can be converted into compound 53 by Process A, B, C or D.
[Process 12]
Compound 55 can be synthesized by subjecting compound 54 to reactions analogous to Process 3. Compound 54 can be synthesized according to documented methods (Drugs Future, 1978, 3, 211-215; J. Med. Chem., 1967, 10, 78-84; J. Med. Chem., 1998, 41, 2928-2931).
[Process 13]
Compound 56 can be converted into compound 57 by the following steps: 1) 1,2-addition with Xxe2x80x94Mgxe2x80x94(CH2)mOR12, 2) dehydration, 3) reduction and 4) deprotection (R12), and then subjected to reactions analogous to Scheme E to give compound 58.
[Process 14]
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound 59 is reacted with chiral olefin 60 in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound 61. Compound 61 is then subjected to the following reactions in the order stated, (a) reduction, deprotection and hydrolysis or (b) reduction, hydrolysis and deprotection, to give compound 62.
(a) Reduction, Deprotection and Hydrolysis
1) Reduction
In the presence of a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound 61 is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give a reduction product.
2) Deprotection
Next, deprotection of the phenolic hydroxyl group is carried out to give a deprotected product.
3) Hydrolysis
By way of example, if R* is a group of formula 63, the deprotected product is further treated with lithium hydroxide, sodium hydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogen peroxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in a solvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/water mixture, a dioxane/water mixture, a dimethoxyethane/water mixture, a methanol/water mixture, an ethanol/water mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give compound 62.
(b) Reduction, Hydrolysis and Deprotection
1) Reduction
In the presence of a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound 61 is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give a reduction product.
2) Hydrolysis
By way of example, if R* is a group of formula 63, the reduced product is further treated with lithium hydroxide, sodium hydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogen peroxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in a solvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/water mixture, a dioxane/water mixture, a dimethoxyethane/water mixture, a methanol/water mixture, an ethanol/water mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give a carboxylic acid.
3) Deprotection
Next, deprotection of the phenolic hydroxyl group is carried out to give compound 62.
The chiral olefin of formula 60 used in the above process can be synthesized as shown in Reaction Scheme 15.
[Process 15]
[Synthesis of Chiral Olefin]
In the presence of a base (e.g., lithium diisopropylamide, lithium hexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) and HMPA, compound 67 is reacted with R2(CH2)n-L1 in an inert solvent (e.g., tetrahydrofuran, toluene, diethyl ether, hexane, preferably tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9230xc2x0 C. to room temperature, to give compound 60.
Chiral olefin 60 can also be synthesized in the following manner.
In the presence of a base (e.g., lithium diisopropylamide, lithium hexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) and HMPA, compound 68 is reacted with compound 69 in an inert solvent (e.g., tetrahydrofuran, toluene, diethyl ether, hexane, preferably tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9230xc2x0 C. to room temperature, to give compound 60.
[Process 16]
Compound 70 can be converted into compound 73 by a procedure analogous to Process 14.
[Process 17]
Compound 75 having substituents R21., R22, R23 and R24 on its benzene ring can be converted into compound 77 by a procedure analogous to Process G. Each of R21, R22, R23 and R24 independently represents a hydrogen atom, a linear or branched C1-C5 alkyl group, a linear or branched C1-C7 halogenoalkyl group, a halogen atom or an acyl group.
[Process 18]
Compound 78 is reacted with compound 79 in the presence of a base to give compound 80. Compound 81 can be synthesized from compound 80 according to Processes 3 and K.
[Process 19]
Compound 82 synthesized according to the method described in J. Med. Chem., 1057(1984) is subjected to Friedel-Craft reaction with compound 83 and then treated according to Process 3.